Summary Antibiotic resistance is a foremost public health concern worldwide. The Harvard-wide Program on Antibiotic Resistance was specifically designed to be responsive to this global urgency. It has as its theme and overarching goal ?Development of new approaches for treating and preventing multidrug resistant MRSA and VRE infection.? A team of highly collaborative and productive scientists from diverse fields ? ranging from medicine to molecular genetics to biochemistry ? was recruited to this effort. The previous funding period was highly productive, with major achievements including: 1) taking novel and unique approaches to identify and develop lead compounds for inhibition of wall teichoic acid biosynthesis by S. aureus; 2) identifying and pursuing new cell wall targeting activities; 3) using a unique screening strategy to identify non-toxic compounds that target the bacterial membrane, including repurposing drugs already in use; 4) identifying features of S. aureus that are important for its ability to exist and proliferate at the site of infection; 5) developing field-leading tools for target identification; and 6) determining the characteristics of efflux pumps that impede intracellular antibiotic accumulation. To build on these successes, the team identified the most promising avenues growing out of the previous period, and designed lines of research along the shortest pathway for solving the antibiotic resistance problem. These include 1) Applying powerful new technologies in novel ways, discover what factors limit the effectiveness of existing antibiotics; 2) Using new approaches to drug discovery that take advantage of novel screens developed in the initial period, and advance the top leads; and 3) Developing new paradigms for patient management that reduce the probability of development of highly antibiotic resistant infection. The above aims will be achieved by 4 subprojects functioning collaboratively as an interactive network that capitalizes on and maximizes the use of all program assets. As projects have grown together, synergy has stemmed from both intellectual and material contributions. Fiscal and functional management will be overseen by an experienced Administrative Core, which also serves to promote data sharing and connect the project to the greater academic and pharmaceutical communities through organizing the annual BAARN meeting and other activities.